Treating Duchenne Cardiomyopathy in the Mouse Model by Gene Repair
Abstract
The goal of this project is to test adeno-associated virus (AAV) CRISPR (clustered regularly interspaced palindromic repeat) gene editing therapy for Duchenne cardiomyopathy in the mdx model. In the previous funding period, we performed AAV CRISPR therapy in young adult male mdx mice. We observed widespread dystrophin restoration in the heart on immunostaining. However, we did not detect dystrophin expression in skeletal muscle. Further cardiac dystrophin restoration is too low to restore hemodynamic function. In the last funding period, we discovered the underlying mechanism that is responsible for the low CRISPR efficiency in our original study. To determine whether long-term CRISPR therapy can improve cardiac function, we performed the study in female mdx mice because female mice show more severe cardiac disease than male mice. Based on the finding, we also changed our strategy. Our study showed that the new strategy can enhance CRISPR editing in the heart and improve heart function. However, in our last years study, we did not evaluate whether our new strategy can work in skeletal muscle. In the current funding period, we performed the study in male mice using our new strategy. We used male mice because they show more severe skeletal muscle disease than female mice. Similar to what we saw in female mice, we found our new strategy also significantly enhanced CRISPR editing in skeletal muscle. Specifically, we observed significantly higher dystrophin restoration than what we saw in our original study. Further, we observed reduction in skeletal muscle fibrosis and increase in muscle force. Our results in male mice confirmed and extended our study in female mice. To further understand whether local dystrophic micro-environment underlies our observation, we performed local injection study. In sharp contrast to our finding in systemic injection, the new strategy yielded similar gene editing efficiency as the original strategy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2019
- Accession Number
- AD1086315
Entities
People
- Adrianne Pittman
- Charles A. Gersbach
- Dongsheng Duan
- Gary Yao
- Matthew Gemberling
- Nalinda Wasala
- Yi Lai
- Yongping Yue
Organizations
- University of Missouri System